Cataract is a leading cause of vision loss and accounts for -45% of blindness worldwide. Epidemiological studies have shown that cataract is a multi-factorial disease involving genetic and environmental factors. The goal of this study is to improve understanding of the molecular genetic basis of cataract. The proposal has three specific aims. In specific aim 1, we will use cell transfection and transgenic mouse techniques to characterize the pathogenic effects of a mutation in a novel gene for inherited cataract. In specific aim 2, we will use expression-profiling and mutation-profiling techniques to identify a novel gene for inherited cataract. In specific aim 3, we will use a custom re-sequencing array to test for association between genes for inherited cataract and age-related cataract. Results from these genetic studies will 1) provide new insights regarding the molecular basis of lens development and aging, 2) contribute to the design of gene-based diagnostics and therapeutics for cataract management, and 3) enable better evaluation of the gene-gene versus gene-environment interactions underlying cataract development. Public health relevance: Cataract afflicts more than 20 million Americans over age 40 and is the most common reason for eye surgery, accounting for -60% of the Medicare vision budget. Cataract is also a significant cause of visual impairment in childhood. This research aims to identify and characterize genetic factors that cause cataract to run in families and develop new ways to diagnose, treat and even prevent cataract.